The present invention relates to cationic peptides having antibiotic activity.
Methicillin-resistant strains of Staphylococcus aureus (MRSA) cause infections that are refractory to standard anti-staphylococci antibiotics, and in many cases vancomycin is the antibiotic of last resort. Consequently, it is of great concern that vancomycin-resistant strains of MRSA may develop.
Infections due to enterococci have been difficult to treat for many years because these organisms are intrinsically resistant to many antibiotics. Ampicillin has been the mainstay for treatment of uncomplicated enterococcal infections, but many strains have now become resistant to ampicillin. vancomycin is again the only effective treatment for these ampicillin-resistant enterococcal infections. In the past few years, vancomycin-resistant enterococcal strains(VRE) have begun to appear and they are rapidly spreading across North America. There are no effective antibiotics currently available for such organisms and the recent report of an outbreak of VRE with a 73% mortality rate has highlighted the seriousness of the situation, See Edmond, M. B. et al., Clinical Infections Diseases 20: 1126-33, 1995.
New compounds are needed for the treatment of antibiotic-resistant pathogens, particularly gram positive strains of human pathogens. The present invention is directed to fulfilling this need, and provides related advantages as described herein.
This invention provides an antibiotic peptide of formula (1): 
wherein:
a, b, and c are independently selected integers, wherein a=1-10, b=1xe2x88x9210, and c=2-5;
Y is selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms;
LPAA is an amino acid residue having the structure xe2x80x94NXxe2x80x94Cxcex1R1xe2x80x94COxe2x80x94, wherein for each LPAA in the peptide, R1 is independently selected from the group consisting of: hydrogen; a linear, branched or cyclic, saturated or unsaturated alkyl containing one to ten carbons atoms optionally substituted with xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F xe2x80x94CN, xe2x80x94O2CR, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSR, xe2x80x94SOR, or xe2x80x94SO2R; benzyl, in which a phenyl ring of the benzyl is optionally substituted with R, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSR xe2x80x94NO2, xe2x80x94SOR, or xe2x80x94SO2R; and, arylalkyl in which an alkyl group of the arylalkyl has two to ten carbon atoms and is linear, branched or cyclic, saturated or unsaturated, optionally substituted with xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSR xe2x80x94NO2, xe2x80x94SOR, or xe2x80x94SO2R, and in which an aryl ring of the arylalkyl is phenyl, or indole, optionally substituted with R, xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl xe2x80x94CN, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSR xe2x80x94NO2, xe2x80x94SOR, or xe2x80x94SO2R; wherein for R1. R is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms, and providing that when R1 is joined to Cxcex1 by a single bond, H is also present joined to Cxcex1; and, for each LPAA in the peptide, X is independently selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons;
BAA is an amino acid residue having the structure xe2x80x94NXxe2x80x94CHR2xe2x80x94COxe2x80x94, wherein for each BAA in the peptide, R2 is independently selected from the group consisting of: a linear, branched or cyclic, saturated or unsaturated alkyl group of one to ten carbons, substituted with one of NH2, NRH, NR2, NR3+, guanidinyl (xe2x80x94NHxe2x80x94CNHxe2x80x94NH2), and imidazole, and optionally substituted with xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94O2CR, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSR, xe2x80x94SOR, or xe2x80x94SO2R; benzyl in which a phenyl ring of the benzyl is substituted with one of NH2, NRH, NR2, NR3+, and optionally substituted with R, xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSR xe2x80x94NO2, xe2x80x94SOR, or xe2x80x94SO2R; arylalkyl in which an alkyl of the arylalkyl is linear, branched or cyclic, saturated or unsaturated of two to ten carbons, optionally substituted with xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2xe2x80x94CONHR, xe2x80x94CON2, xe2x80x94COSR, xe2x80x94NO2, xe2x80x94SOR, or xe2x80x94SO2R, and in which an aryl ring of the arylalkyl is phenyl substituted with one of NH2, NRH, NR2, NR+, indole substituted with one of NH2, NRH, NR2, NR3+, pyridine, or imidazole; and wherein the aryl ring is optionally substituted with R, xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSR xe2x80x94NO2, xe2x80x94SOR, or xe2x80x94SO2R; wherein for R2, R is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms; and, for each BAA in the peptide X is independently selected from the group consisting of: H; OH; and a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbons; and,
R3 and R4=R1, and R3 and R4 are the same or different.
The term LPAA denotes an amino acid residue having a lipophilic character as compared to BAA. For example, LPAA includes the amino acids glycine, alanine, valine, butyrine, leucine, isoleucine, asparagine, glutamine, tryptophan, tyrosine, phenylalanine, methionine, methionine sulfoxide, threonine, serine, cysteine, and the xcex1,xcex2-unsaturated analogs of these amino acids except glycine. The term BAA denotes an amino acid residue having a basic character as compared to LPAA. For example, BAA includes the amino acids ornithine, lysine, histidine, and arginine.
The peptide of formula (1) has an N-terminus modified by the presence of an alpha hydroxy acyl group, and a C-terminus reduced to a primary alcohol. R3 at the N-terminus may be an alkyl group such as xe2x80x94CH(CH3)CH2CH3 as is the case for Bogorol A-D as disclosed herein. At the C-terminus, Y in formula (1) may be hydrogen and R4 may be xe2x80x94CH(CH3)2, as is the case for Bogorol A-D described herein.
The values of each a, b, and c integer in formula (1) are independently selected The structure of each BAA or LPAA in the peptide may be the same or different as compared to any other BAA or LPAA in the peptide. The number of LPAA components may differ as between different regions along the linear structure of the peptide. Thus, each-[-BAA-(-LPAA)b-]-unit of the peptide may have a different BAA residue, different value for b, and different LPAA residues, as compared to any other such unit.
A peptide of formula (1) preferably will have from 10-25 LPAA and BAA residues combined, more preferably from 10-20 and even more preferably from 12-18, which numbers do not include the C-terminal modified amino acid residue Preferably, the number of BAA residues (denoted by the integer c), will be 2-3. Bogorol A-D have a total of 12 LPAA and BAA residues combined, which when added to the modified C-terminal residue, results in a total of 13 amino acid and modified amino acid residues, including 3 BAA residues. Preferably the integer b will be 2-6, more preferably 2-4, and most preferably 2-3. Each BAA residue is preferably separated by from 2-4 and more preferably 2-3 LPAA residues, which means that the integer b is 2-4 or 2-3, but not necessarily at the C-terminus of the peptide. Preferably, the number of LPAA residues at each of the N and C termini of the peptide will be 1-5, more preferably 1-3 and most preferably, 2.
Peptides of this invention may be ordered such that a basic side group of each BAA is aligned along an axis parallel to a central axis of the peptide when the peptide is in an xcex1-helix configuration. This ordering may be achieved by spacing each BAA residue according to the number of residues in each turn of such a helix and providing a particular stereochemical configuration for each BAA residue. For example, the stereochemical configuration of the ornithine and lysine residues of Bogorol A-D (from the N to the C terminus) may be D, D, L or D, L, D, with each of these basic amino acid residues being separated by 2-3 (preferably 3) LPAA residues.
Preferred peptides of this invention have one or more of the following limitations:
1) LPAA is an amino acid selected from the group consisting of: glycine; alanine; valine; butyrine; leucine; isoleucine; asparagine; glutamine; tryptophan, tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; serine; cysteine; and xcex1,xcex2-unsaturated analogs of each of said amino acids except glycine; BAA is selected from the group consisting of: ornithine; lysine; histidine; and arginine; and, R3 and R4 are independently selected from the group consisting of: hydrogen; methyl; ethyl; n-propyl; isopropyl; n-butyl; isobutyl; sec-butyl; benzyl; and, p-hydroxybenzyl;
2) LPAA is selected from the group consisting of: valine; leucine; isoleucine; tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; and dehydrobutyrine (DBH); BAA is selected from the group consisting of: ornithine; lysine; and arginine; and, R3 and R4 are independently selected from the group consisting of: hydrogen; methyl; ethyl; n-propyl; isopropyl; n-butyl; isobutyl; sec-butyl; benzyl; and p-hydroxybenzyl;
3) LPAA is selected from the group consisting of: valine; leucine; isoleucine; tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; and dehydrobutyrine (DBH); BAA is selected from the group consisting of: ornithine; lysine; and arginine; and, R3 and R4 are independently selected from the group consisting of: isopropyl; isobutyl; and sec-butyl;
4) a is 1-5; c is 2-5; b is 2-6; and
5) a is 2; c is 3; b is 2-3.
Preferred peptides of this invention may comprise (in a N to C terminal direction) a tyrosine-isoleucine dipeptide as the two LPAA residues immediately preceding the modified C-terminal amino acid residue. Preferred peptides may also comprise (in a N to C terminal direction) the following sequence of amino acid residues: (leucine, methionine, or valine)-ornithine-isoleucine-valine-valine-lysine-valine-leucine-lysine. Preferred peptides may also comprise DHB or threonine (preferably DHB) as the LPAA at the N-terminus of the peptide. When an LPAA comprises R1 joined to the xcex1-carbon of the residue (Cxcex1) by a single bond, hydrogen is also joined to Cxcex1, as would be the case for a common amino acid such as valine or leucine. When an LPAA comprises R1 joined to Cxcex1 by a double bond (such as is the case for DHB), there is no hydrogen joined to Cxcex1.
Naturally occurring peptides of this invention are provided as isolated peptides, i.e. in a substantially purified form. A substantially purified form is one wherein one or more peptides of this invention constitute at least about 1 weight percent of a composition, preferably at least about 10 weight percent, more preferably at least about 30 weight percent, still more preferably at least about 50 weight percent, yet still more preferably at least about 70 weight percent, and yet still more preferably at least about 95 weight percent, and most preferably at least about 99 weight percent.
Peptides of this invention may be provided as salts, which salts include acid or base addition salts, depending on whether the moiety on the peptide (e.g. an amino acid side group) being connected to a salt is a basic or acidic moiety. Preferably, the salt will be acceptable for pharmaceutical purposes.
This invention also provides peptides of this invention and pharmaceutically acceptable salts thereof, in a pharmaceutical composition. A pharmaceutical composition of the invention may not necessarily contain a peptide of this invention in a substantially purified form because the composition may contain carriers, diluents, or other materials suitable for use in pharmaceutical compositions, in admixture with the peptide.
This invention also provides a method of treating bacterial infection, comprising administering to a patient having a bacterial infection, an effective amount of a peptide, peptide salt, or pharmaceutical composition of this invention. Preferably, the effective amount will be sufficient to relieve one or more symptoms associated with or due to the bacterial infection.
This invention also provides the use of a peptide, peptide salt, or a pharmaceutical composition of this invention as an antibiotic. Such antibiotic use includes use for the treatment of bacterial infections, including infections by gram-positive bacteria.
This invention also provides the use of a peptide, peptide salt, or pharmaceutical composition of this invention for the preparation of an antibiotic medicament. Such a medicament may be suitable for use against bacteria, including gram-positive bacteria.
Peptides of the invention include the solvates, salts (acid-or base-addition salts, depending on whether the amino acid sidechain being converted to a salt is basic or acidic, respectively), and derivatives or analogs such as esters (derivatives of alcohol functionalities on the C and N terminal residues and/or a tyrosine phenol), amines (derivatives of amino acid sidechains containing an amino group), ethers (derivatives of amino acid and N- and C-terminal modified amino acid sidechains containing an hydroxyl group) and amides (derivatives of amino acid sidechains containing either an amine or carboxylic acid group).
Salts may contain at least one negatively charged ion selected from chloride, bromide, sulfate, phosphate, C1-15 carboxylate, methanesulfonate and p-toluenesulfonate, which are exemplary only. Exemplary C1-15 carboxylates include acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartarate, citrate, ascorbate, maleate, hydroxymaleate, benzoate, hydroxybensoate, phenylacetate, cinnamate, salicylate and 2-phenoxybenzoate.
Salts may contain at least one positively charged ion selected from lithium, sodium, potassium, beryllium, magnesium, calcium and quaternary ammonium ions, which are exemplary positively charged ions. Exemplary quaternary ammonium ions include tetraalkylammonium, and trialkylaralkylammonium ions.
Derivatives or analogs may have an amine group of an ornithine or lysine sidechain being a secondary, tertiary or quaternary amine group. Other amino acid sidechains may be in a derivative form as well. Exemplary ornithine or lysine sidechains have the formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NHR, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R)2 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R)3 wherein R is an alkyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an acyl group that may be of straight chain, or where possible of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities.
In other derivatives, a hydroxyl group of a tyrosine sidechain, a hydroxyl group of the xcex1-hydroxy acyl N-terminal residue, or the primary alcohol of the C-terminal residue may be converted to an ether or ester group, and other amino acid sidechains are optionally in a derivative form as well. For example, a tyrosine sidechain may have the formula xe2x80x94CH2xe2x80x94C6H4xe2x80x94Oxe2x80x94R, wherein C6H4 is an aromatic ring and xe2x80x94Oxe2x80x94R is in the para position, and R is a C1-15 alkyl group so as to form an ether where the alkyl group may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or a C1-15 acyl group so as to form an ester, where the acyl group may be of straight chain, or where possible, of cyclic or branched structure and contain one or more alkene, alkyne, or aromatic functionalities.
Peptides of this invention include peptides having a xe2x80x9cnon-naturalxe2x80x9d stereochemistry at one or more of the carbons of the component amino acids as well as either epimer of the modified C- and N-terminal residues. The term xe2x80x9cnon-naturalxe2x80x9d refers to stereochemistry that differs from that of naturally occurring peptides of this invention, such as Bogorol A. In structural formula of naturally occurring peptides such as Bogorol A as set out herein, xe2x80x9cnaturalxe2x80x9d stereochemistry may be indicated by wedged and dashed lines according to the standard stereochemical convention. Use of xe2x80x98wavyxe2x80x99 lines attached to a chiral center indicates that no particular configuration is represented by the formula.
This invention is directed to various analogs of naturally occurring compounds. In the below-listed structure, no stereochemistry is designated because the analogs of the invention may have any possible stereochemistry at each atom capable of having more than one stereochemical arrangement of substituents.
Peptides of this invention may be described in terms of formula (2): 
wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 may independently be hydrogen; or a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons optionally substituted with xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NHR2, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR2xe2x80x94CONR2, xe2x80x94COSH, xe2x80x94COSR xe2x80x94NO2, xe2x80x94SO3xe2x80x94, xe2x80x94SOR, xe2x80x94SO2R, xe2x80x94NHxe2x80x94CNxe2x80x94NH2 (guanidinyl); or benzyl where the phenyl ring may be substituted with R, xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NHR2, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSH, xe2x80x94COSR xe2x80x94NO2, xe2x80x94SO3xe2x80x94, xe2x80x94SOR, xe2x80x94SO2R; or arylalkyl where the alkyl group may be linear, branched or cyclic, saturated or unsaturated containing two to ten carbons that may be substituted with xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NHR2, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSH, xe2x80x94COSR xe2x80x94NO2, xe2x80x94SO3xe2x80x94, xe2x80x94SOR, xe2x80x94SO2R and where the aryl ring may be phenyl, indole, or imidazole substituted with R, xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NHR2, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSH, xe2x80x94COSR xe2x80x94NO2, xe2x80x94SO3xe2x80x94, xe2x80x94SOR, xe2x80x94SO2R; and R is a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons. Preferred analogs may have one to four amino acid residue as present in Bogorol A replaced with a different amino acid residue.
In another aspect, peptides of this invention are linear compounds which may be described in terms of the shorthand structure shown below. 
In Formula A, AA2 through AA13 are generic symbols, each representing an amino acid residue, or a salt or derivative thereof as defined herein. RA14 represents a modified carboxyl terminal amino acid where the carboxyl group has been reduced to a primary alcohol (e.g. valinol). xcex1OHAA1 represents an alpha hydroxy acid modified residue. Each line between neighbouring (attached) residues represents an amide (also known as a peptide) bond formed between neighbouring residues, as well as the isosteres thereof. xe2x80x9cIsosterexe2x80x9d means a modified form of the normal peptide bond (xe2x80x94C(O)NHxe2x80x94) between attached amino acid residues, such as xe2x80x94CH2NHxe2x80x94 (reduced), C(O)N(SH3) (N-methylamide), xe2x80x94COCH2xe2x80x94 (keto), xe2x80x94CH(OH)CH2xe2x80x94 (hydroxy), xe2x80x94CH(NH2)CH2xe2x80x94 (amino), xe2x80x94CH2CH2xe2x80x94 (hydrocarbon), or xe2x80x94NHC(O)xe2x80x94 (inverted normal peptide bond). Preferably the compounds of the present invention are not in isosteric forms.
Except where otherwise stated, throughout this specification the recitation of a compound denotes all possible isomers within the structural formula given for those compounds, in particular optical isomers. Unless otherwise stated definitions are to be regarded as covering mixtures of isomers, and individual isomers, including racemic mixtures, where they can be resolved.
The compounds of the present invention contain multiple asymmetric carbon atoms and thus exist as enantiomers and diastereomers. Unless otherwise noted, the present invention includes all enantiomeric and diastereomeric forms of the compounds. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the invention are included within the scope of the present invention. Also included are epimers of the C and N terminal modified amino acids.
Except if otherwise stated, definitions of compounds in this specification may be regarded as covering all possible esters of the compounds. In particular, except if otherwise stated, the recitation of amino acid residue having a carboxylic acid group is to be regarded as a recitation of all possible esters of that carboxylic acid.
Except if otherwise stated, definitions of compounds in this specification having phenolic groups may be regarded as covering all possible ethers or esters of the phenolic hydroxyl group.
Peptides of this invention may be described in terms of formula (3) shown below: 
wherein:
R1, R2, and R3 may independently represent a hydrogen atom: or an alkyl group that may be of straight chain or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an acyl group that may be of straight chain, or where possible, of cyclic or branched structure and way contain one or more alkene, alkyne, or aromatic functionalities.
Peptides of this invention may also be described in terms of Formula B. 
wherein:
R1 R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 may independently be hydrogen; or a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons optionally substituted with xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NHR2, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2R, xe2x80x94CHO xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSH, xe2x80x94COSR, xe2x80x94NO2, xe2x80x94SO3xe2x80x94, xe2x80x94SOR, xe2x80x94SO2R, xe2x80x94NHxe2x80x94CNxe2x80x94NH2 (guanidinyl); or benzyl where the phenyl ring may be substituted with R, xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NHR2, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSH, xe2x80x94COSR, xe2x80x94NO2, xe2x80x94SO3xe2x80x94, xe2x80x94SOR, xe2x80x94SO2R; or arylalkyl where the alkyl group may be linear, branched or cyclic, saturated or unsaturated containing two to ten carbons that may be substituted with xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NHR2, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSH, xe2x80x94COSR, xe2x80x94NO2, xe2x80x94SO3xe2x80x94, xe2x80x94SOR, xe2x80x94SO2R and where the aryl ring may be phenyl, indole, or imidazole substituted with R, xe2x80x94OH, xe2x80x94OR, xe2x80x94O2CR, xe2x80x94SH, xe2x80x94SR, xe2x80x94SOCR, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NHR2, xe2x80x94NHCOR, xe2x80x94I, xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2R, xe2x80x94CHO, xe2x80x94COR, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94COSH, xe2x80x94COSR, xe2x80x94NO2, xe2x80x94SO3xe2x80x94, xe2x80x94SOR, xe2x80x94SO2R; and R is a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons.
Peptides of this invention include the following peptides termed Bogoral A-D: 
The compounds of the present invention may be prepared in vitro, using solid phase or solution peptide synthesis techniques, or may be prepared in vivo, from micro-organism ATCC 55797. Solution phase techniques as set forth in K. Okamato, K. et al. Bull. Chem. Soc. Jpn. 50:231-236 (1977), Ohno, M. et al. J. Am. Chem. Soc. 88(2):376-377 and Kosui, N. et al. Int. J. Peptide Protein Res. 18:127-134 (1981) may be modified to prepare the linear peptides of the present invention, merely by appropriate substitution of the suitably protected amino acids, reduced amino acids, or xcex1-hydroxy acids. The compounds of the invention may also be isolated from micro-organism ATCC 55797 under appropriate conditions.
Ion exchange techniques can be used to prepare the various salts of the invention, where such techniques are well known in the art. For example, hydrochloric acid may be added to a neutral compound of the invention to prepare the hydrochloride salt thereof. Dialysis techniques may also be employed effect ion exchange and so obtain a desired salt of the invention from another salt of the invention.
The isolation and synthesis procedures described herein, especially when taken with the general knowledge in the art, provide sufficient guidance to those of ordinary skill in the art to perform the synthesis, isolation, and purification of the compounds described herein and other analogous compounds. Individual enantiomers may be obtained, if desired, from mixtures of the different forms by known methods of resolution, such as the formation of diastereomers, followed by recrystallisation. Alternatively, isomerically pure starting materials may be employed in the synthesis of a compound of the invention or various diastereomers may be separated by chromatography.
Peptides of this invention have utility as antibiotics, and may be used and administered in a manner analogous to antibiotics (particularly antibiotic peptides) known in the art, to provide the beneficial effects desired of antibiotics. The modified linear peptides of the invention may be used against gram negative and gram positive bacteria, but are particularly effective against gram-positive bacterial including Staphylococcus aureus and Enterococcus faecalis. 
In using a peptide of this invention, the peptide is preferably administered to a patient in a pharmaceutical (including veterinary) composition comprising a pharmaceutically acceptable carrier, and optionally, one or more other biologically active ingredients. Such compositions may be in any form used for oral, topical, vaginal, parenteral, rectal and inhalatory application. The compositions may be provided in discrete dose units. The carriers may be particulate, with compositions being, for example, tablets or powders, or liquid, with the compositions being for example, oral syrups or injectable liquids, or gaseous, for inhalatory application.
For oral administration, an excipient and/or binder may be present. Examples are sucrose, kaolin, glycerin, starch destrins, sodium alginate, carboxymethylcellulose and ethyl cellulose. Coloring and/or flavoring agents may be present. A coating shell may be employed. For rectal administration oleaginous bases may be employed, for example, lanolin or cocoa butter. For an injectable formulation, buffers, stabilizers and isotonic agens may be included.
It will be evident to those of ordinary skill in the art that the optimal dosage of a peptide or pharmaceutical composition of this invention may depend on the weight and physical condition of the patient, on the severity and longevity of We illness; and on the particular form of the active ingredient, the manner of administration and the composition employed.
A peptide of this invention may be used in therapy with the peptide being bound to an agent, for example, a monoclonal or polyclonal antibody, a protein or a liposome, which assist the delivery of the peptide to the site of infection.
In a further embodiment, the present invention provides a method for the treatment of a patient afflicted with a bacterial infection comprising the administration thereto of a therapeutically effective amount of a compound or composition of this invention.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to an amount which is effective, upon single or multiple dose administration to the patient, in providing relief of symptoms associated with bacterial infections. As used herein, xe2x80x9crelief of symptomsxe2x80x9d of a bacterial infection refers to a decrease in severity over that expected in the absence of treatment and does not necessarily indicate a total elimination or cure of the infection or condition caused thereby. In determining the therapeutically effective amount or dose, a number of factors are considered by the attending diagnostician, including, but limited to; the species of mammal; its size, age, and general health; the specific infection involved; the degree of or involvement or the severity of the infection or condition arising therefrom; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
As used herein, the term xe2x80x9cpatientxe2x80x9d refers to a warm-blooded animal such as a mammal which is afflicted with a particular inflammatory disease state. It is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals within the scope of the meaning of the term.
A therapeutically effective amount of a compound of Bogorol A is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are expected to vary from about 0.5 to about 10 mg/kg/day.
In effecting treatment of a patient afflicted with a condition described above, a compound or composition of this invention can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral, aerosol, and parenteral routes. For example, compounds can be administered orally. by aerosolization, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like. Oral or aerosol administration is generally preferred. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition, and other relevant circumstances. See, eg., Remington""s Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990).
Peptides or salts of peptides of this invention can be administered alone or in the form of pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
In another embodiment, the present invention provides peptides or salts of peptides in admixture or otherwise in association with one or more inert carriers. These compositions are useful, for example, as assay standards, as convenient means of making bulk shipments, or as pharmaceutical compositions. An assayable amount of a compound of this invention is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts will generally vary from about 0.001T to 75% of the composition by weight. Inert carriers can be any material which does not degrade or otherwise covalently react with the compound. Examples of suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients.
The pharmaceutical compositions of this invention may be prepared in manners well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, or the like.
The compounds or compositions of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of the compound of the invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the compound present in compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 5.0-300 milligrams of a compound of the invention. The tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavours. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administration, the compounds of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1 and about 50% of the weight thereof. The amount of the inventive compound present in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 5.0 to 100 milligrams of the compound of the invention.
Compounds or compositions of the present invention may also be administered by aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredients. Aerosols may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient. Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like. Preferred aerosols are able to be determined by one skilled in the art.
The compounds or compositions of this invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base. The base, for example, may comprise one or more of the following: petrolaum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Topical formulations may contain a concentration of the compound of this invnention of from about 0.1 to about 10% w/v (weight per unit volume).
Solutions or suspensions according to this invention may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of toxicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
Peptides or peptide salts of the invention may be combined with one or more known antibiotics to provide a composition having a particularly desired efficacy.
The following examples are offered by way of illustration and not by way of limitation.